JP2588265B2 - Heterocyclic compounds - Google Patents

Abstract

Heterocyclic urea and carbamate cpds. of formula A-X-NH-CW-Y-B (I) and pharmaceutically acceptable acid addn. salts are new where A is aromatic gp. of formula (A1)-(A4). R1 is H or one or more of lower alkyl, lower alkoxy, OH, halogen, lower haloalkyl, NH2, NO2, carboxamido, phenyl(lower) alkoxy (where phenyl is opt. substd. by lower alkyl, lower alkoxy or halogen substit(s).), acylamino or mono- or di-lower slkylamino, Z1-Z2 are CH2-CH, NR2-CH, 0-CH, -S-CH, CH2-N, O-N, S-N, NR2-N, CH-NR2 or N-NR2, R2 is H, lower alkyl or phenyl or phenyl(lower)alkyl where phenyl is opt. substd. by lower alkyl, lower alkoxy or halogen substit(s).; Z2-Z4 are CH:CH, O-CH2 or N:CH, Z5 is N or CH, Z6 is O, S or NH; X is a bond or -CO-, W is O or S, Y is NH or O, B is satd. azacyclic ring of formula (B1-(B5) or N-oxide of (B2), n is 2, 3 or 4, R3 is H or lower alkyl, m is 1, 2 or 3, p is 0, 1 or 2 and R4, R5 are H or lower alkyl, with the proviso that when X is bond, A is (A3) or (A4) and W is O, then (A3) or (A4) does not contain a substit. ortho to the -X-NH-Cw-Y-B side chain.

Description

Description: FIELD OF THE INVENTION The present invention relates to heterocyclic compounds. For more information,
The present invention relates to novel aryl or aroyl urea or carbamic acid derivatives and the corresponding thio analogs, their preparation, their use and pharmaceutical compositions containing them.

DISCLOSURE OF THE INVENTION The novel compounds of the present invention are useful as antagonists of specific 5-hydroxytryptamine (5-HT) receptors as described below. Certain related aryl urea and carbamic acid derivatives are disclosed in European Patent Application No. 2358
No. 78 and No. 255297.

The novel heterocyclic compound of the present invention is a compound represented by the formula: AX-NHCW-YB (I) and a pharmaceutically acceptable acid addition salt thereof. In the formula (I), A is a formula: Wherein the free valence is attached to the fused ring of either formula (a) or (b), and R ¹ is hydrogen or lower alkyl,
Lower alkoxy @ lower alkyloxy (eg, methoxy, ethoxy, propoxy or butoxy), cyclo (lower) alkyloxy, cyclo (lower) alkyl-lower alkyloxy (eg, cyclopropylmethoxy), (lower) alkenyl (lower) alkyl Oxy (e.g., allyloxy) and loha (lower) alkyloxy {, hydroxy, halogen (e.g., chlorine), halo (lower) alkyl (e.g., trifluoromethyl), amino, nitro, carboxamide, phenyl groups are optionally Phenyl (lower) alkyloxy, (lower) alkylamino, optionally substituted by one or more lower alkyl, lower alkyloxy or halogen substituents;
One or more selected from di (lower) alkylamino or acylamino {eg, (lower) alkanoylamino or halo (lower) alkanoylamino} (eg,
1 to 3) identical or different substituents, Z ¹ -Z ² is CH ₂ -C
^{H, NR 2 -CH, O-} CH, S-CH, CH 2 -N, O-N, S-
N, NR ² —N, CH—NR ² or N—NR ² , R ² is hydrogen, (lower) alkyl or phenyl, optionally substituted by one or more lower alkyl, lower alkyloxy or halogen substituents Phenyl or phenyl (lower) alkyl, Z ³ -Z ⁴ is CH ＝ CH, O—CH ₂ or N ＝ CH, Z ⁵ is N or CH and Z ⁶ is O, S or NH
X represents a direct bond or CO, W represents oxygen or sulfur, Y represents NH or O, and B represents the formula (II): Wherein n represents 2, 3 or 4 and R ³ represents hydrogen or (lower) alkyl; formula (III): Or its N-oxide, formula (IV): [Wherein m is 1, 2 or 3 and R ³ is the same as above],
Formula (V): [Wherein p represents 0, 1 or 2], or the formula (VI): [Wherein, R ⁴ and R ⁵ each represent hydrogen or lower alkyl]. However, when X is a direct bond, A is a group represented by the formula (c) or (d), and W is oxygen, the ring (c) or (d) is -X-NH
No substituent at the ortho position to the CW-YB side chain.

The term "lower" as used herein means that the indicated group has up to 6 carbon atoms.
Preferably, the group has up to 4 carbon atoms. For example, a lower alkyl group may be straight or branched, and may be methyl, ethyl, propyl or butyl.

 X is preferably CO.

When A is a group of the above formula (c), the group has the formula: [Wherein, R ⁶ to R ⁹ are independently hydrogen or the aforementioned substituent
R ¹ means a group represented by the following formula: Particularly preferably,
R ⁶ is lower alkoxy (eg, methoxy) and R ⁷ , R ⁸
And R ⁹ is hydrogen and R ⁶ is lower alkyloxy (eg, methoxy) or cyclo (lower) alkyl (lower) alkyloxy (eg, cyclopropylmethoxy), R ⁷ is hydrogen, R ⁸ is amino or lower. Alkylamino and compounds wherein R ⁹ is halogen (eg, chloro). Other preferred compounds are those in which R ⁷ and R ⁹ are chloro and R ⁶ and R ⁸ are hydrogen.

In the group B of the formula (II), preferably, n is 2 and
R ³ is lower - alkyl, preferably methyl. n is 2
And groups where R ³ is methyl are tropan-3-yl, also known as 8-methyl-8-azabicyclo [3.2.1] octane-
Also known as 3-yl.

The group of formula (III) is known as quinuclidinyl, also known as 1-azabicyclo [2.2.2] octan-3-yl.

In the group of the formula (VI) it is preferred that m is 2 and R ³ is preferably alkyl of 1 to 4 carbon atoms, especially methyl.

In the group of the formula (V), p is preferably 1.

The compounds of the present invention may have one or more asymmetric carbon atoms and the compounds may exist in different stereoisomeric forms. The compounds may exist, for example, as racemates or optically active forms. Optically active forms can be obtained by resolution of the racemates or, in a manner described below, by using optically active form starting materials. Furthermore, groups such as formulas (II) and (IV) may exist in two different configurations corresponding to an end configuration as in tropine and an exo configuration as in pseudotropin. An end arrangement is preferred.

The compounds of the present invention are aryl or aroyl ureas or carbamic acid derivatives (or their corresponding thio analogs) and can be prepared by known methods for preparing urea and carbamic acid derivatives (and thio analogs).

A first general method for preparing the compounds of the present invention is represented by the formula (VI
I): AX-NCW (VII) wherein A, W and X are the same as defined above, by converting an isocyanate or isothiocyanate represented by the formula (VIII): B-YH (VIII) And Y are the same as described above].

Such a reaction can be performed, for example, at room temperature in an organic solvent.

The compound of the present invention wherein Y is NH is a compound of the formula (IX): AX-NHCWNH ₂ (IX) wherein A, W and X are as defined above, B-NH ₂ (X) wherein B is the same as defined above. This method may be performed in the absence of a solvent,
Usually, the reaction is carried out by heating the reactants in the presence of a suitable inert organic solvent such as toluene, pyridine, xylene, chlorobenzene, dimethylformamide or dioxane. Pyridine is the preferred solvent. Often, it is convenient to reflux the reactants in a solvent.

The compound of the present invention wherein X is CO is a compound represented by the formula (XI): NH ₂ CWY-BP (XI) wherein Y, W and B are the same as described above, and a group A-CO- ( A is the same as described above). Examples of acylating agents are reactive derivatives of acids of the formula ACOOH, such as acid halides (eg, acid chlorides) and anhydrides.

The compound of the present invention in which X is a direct bond and Y is NH is an isocyanate or isothiocyanate represented by the formula (XII): B-NCW (XII) XIII): A-NH ₂ (XIII) wherein A is the same as defined above.

A compound of the present invention wherein B is an N-oxide of group (III) can be prepared by oxidizing a compound wherein B is group (III) with, for example, hydrogen peroxide or a peracid.

In any of the above methods, if the reactant has a group that is affected under the reaction conditions used in the reaction, that group may be protected and then the protecting group is removed.

The starting materials for the method are described in the literature or
Or by known methods for analogous compounds.

In the above method, when the compound of the present invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, when the product of the process is a free base, the acid addition salt, particularly a pharmaceutically acceptable acid addition salt, can be prepared by converting the free base to an appropriate organic compound according to conventional procedures for producing acid addition salts from basic compounds. Dissolved in a solvent,
It can be obtained by treating the solution with an acid.

Examples of acid addition salts are sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid,
Salts formed from inorganic and organic acids such as tartaric, fumaric, maleic, citric, acetic, formic, methanesulfonic, p-toluenesulfonic, oxalic and succinic acids.

The compounds of the present invention have pharmacological activity. In particular, the compounds of the present invention antagonize specific 5-hydroxytryptamine (5-HT) receptors in mixed-race animals. In particular, the compounds have 5-HT ₃ antagonistic activity, therefore are useful in conditions antagonism 5-HT ₃ receptor is desirable. 5-HT
₃ -Antagonists are also referred to as "antagonists of the" neuronal "5-hydroxy-tryptamine receptor" and "serotonin (5-hydroxy-tryptamine) M-receptor antagonists". Such compounds include, inter alia, migraine,
It is useful for treating vomiting, anxiety and gastrointestinal disorders and is described as an antipsychotic.

The compound of the present invention can be prepared by the use of Hozard J.R.
rd JR), Naunyn-Schmiedeberg's Arc
h.Phamacol.) 1984, 326, tested for 5-HT ₃ antagonistic activity in the right atrium of the isolated rabbit hearts according to the method of 36-44. This test stimulates 5-HT ₃ receptor existing in the sympathetic nerve endings of the heart, depends on the ability of 5-TH causing the release of arouse noradrenaline an increase in spontaneous heart rate. Antagonistic ability, -log IC ₅₀ (IC ₅₀ is 10 ^-5 M chronotropic responses to 5-HT in the concentration of antagonist that reduces by 50%) represented by.

When tested by this procedure, a representative compound of the present invention, N- (1-azabicyclo [2.2.2] octane-3,
-Yl) -N '-(3,5-dichlorophenyl) urea and N-[[[[1-azabicyclo [2.2.2] octane-3-
Yl] amino] carbonyl] -2-methoxybenzamide, respectively, had -log IC ₅₀ of 8.3 and 8.67. The (S) -enantiomer of the former compound has a -log IC of 9.3.
_{Had 50} .

Compounds of the present invention can be prepared as described in B. Costall et al.
et al.), Neuropharmacology
1987) 26 , 195-200 and JNCrawley et.al., Pharmacology, Biochemistry and Behavior (Pharma).
c. Biochem. Behav.) 1980, 13 , 167-170. Test for anxiolytic activity by a test procedure to measure the exploratory activity of mice in two separate light / dark boxes. I do. The test involved observing several groups of mice in an open box, one third of which was painted black, illuminated under dark red light, painted white, and brightly illuminated. It is separated from the rest of the box. Access to the two sections is through an opening in the center of the divider. Several groups of mice were treated with vehicle or test compound, and exploratory rearining performed by mice in each section.
Measure various behavioral parameters of the animal, including the number of g) and the number of times the mouse crosses the line marked on the floor of each section. For each treatment group, calculate the average number of line intersections and realing in each section of the box. Differences between drug-treated groups and vehicle-treated controls are compared using Student's unpaired t-test. Standard anxiolytics significantly increase exercise and realing in the light section. A test compound is considered to be active if it elicits a series of similar changes, especially if it causes a significant (p <0.05) increase in the realizing activity in the light section of the box. The results for the compounds of the present invention and standard anxiolytics are shown below: Furthermore, the present invention provides a compound or a pharmaceutically acceptable acid addition salt thereof of formula used to antagonize 5-HT ₃ receptor of mammalian (I).

In a further aspect, the invention provides the use of a compound of the invention for the treatment of migraine, vomiting, anxiety, gastrointestinal disorders or psychiatric disorders. The present invention also provides a method for treating migraine, vomiting, anxiety, gastrointestinal disorders or psychotic disorders, comprising administering an effective amount of a compound of the invention to a warm-blooded animal in need thereof.

Obviously, for certain of the aforementioned conditions, the compounds can be used for the prevention and alleviation of acute symptoms. It should be recognized that reference to "treatment" and the like herein includes such prophylactic treatment and treatment of acute symptoms.

The anti-emetic properties of the compounds are particularly useful for treating nausea and vomiting associated with cancer chemotherapeutics and radiation therapy. Thus, the compounds are useful for treating chemotherapeutic agents (cytotoxic or cytostatic agents such as cisplatin, doxorubicin and cyclophosphamide) and radiation. Accordingly, the present invention also provides a product containing a cancer chemotherapeutic agent and a compound of the present invention as a combined preparation for simultaneous, separate or sequential use in the treatment of cancer.

In a further aspect, the invention provides a pharmaceutical composition comprising a compound of the invention in combination with a pharmaceutically acceptable carrier. Any suitable carrier known to those skilled in the art can be used in preparing the pharmaceutical compositions. In such compositions, the carrier will generally be a solid or liquid or a mixture of a solid and a liquid.

Compositions in solid form include powders, granules, tablets, capsules (eg, hard and soft gelatin capsules), suppositories, and pessaries. The solid carrier can be, for example, one or more substances that can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, or tablet-disintegrants. Often,
It may also be an encapsulating material. In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powder or tablet preferably has up to 99%, for example, from 0.03 to 99%, preferably 1 to 80%, of the active ingredient. Suitable solid carriers are, for example,
Includes calcium phosphate, magnesium stearate, talc, sucrose, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.

The term "composition" embraces capsules wherein the active ingredient is formulated with an encapsulating substance as a carrier and the active ingredient (with or without a carrier) is surrounded by the carrier and thus combined with the carrier. Similarly, cachets are also included.

Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as, for example, water, organic solvents, mixtures thereof, or pharmaceutically acceptable oils. Liquid carriers include solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, sedimentation inhibitors, thickeners, coloring agents, viscosity modifiers,
It may contain other suitable pharmaceutical additives such as stabilizers or osmo-regulators. A suitable example of a liquid carrier for oral and parenteral administration is water (particularly an excipient as described above,
Examples include cellulose derivatives, preferably solutions containing sodium carboxymethylcellulose), alcohols (-hydric and polyhydric alcohols such as glycerol and glycol) and derivatives thereof, and oils such as fractionated coconut and peanut oils. I do.
Parenteral carriers may also be liquid esters such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions that are sterile solutions or suspensions can be used for example by intramuscular, intraperitoneal or subcutaneous injection. The sterile solution can also be administered intravenously. When the compound is orally active, it can be administered orally in either liquid or solid composition form.

The compounds of the present invention can also be administered by the nasal route. When formulated for nasal administration, the composition will consist of a compound of the present invention in a liquid carrier, such compositions comprising, for example,
They may be administered in spray form or as drops. The liquid carrier may be water (which may contain additional ingredients to achieve the desired isotonicity and viscosity of the composition). The composition may also have additional excipients such as preservatives, surfactants and the like. The composition is placed in a nasal spray applicator which can administer the composition as a medicament or as a spray. For administration from an aerosol container, the composition also contains a propellant.

The pharmaceutical composition is preferably in unit dosage form, for example, as tablets or capsules. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active component, e.g., containing a packaged powder, vial, ampoule, pre-filled syringe or liquid. It can also be a packaging composition such as a sachet. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

The amount of active ingredient in a unit dose of the composition may be varied if necessary and according to the activity of the active ingredient, or it may be adjusted from 0.5 mg to 750 mg or less.

The present invention also encompasses carrierless compounds where the compound is in unit dosage form.

 Next, the present invention will be described in more detail with reference to examples.

Example 1 N- (1-Azabicyclo [2.2.2] octan-3-yl-N '-(3,5-dichlorophenyl) urea A solution of 1.88 g (10 mmol) of 3,5-dichlorophenyl isocyanate in 20 ml of toluene. At 0 ° C, THF 40ml
In the mixture, 1.26 g (10 mmol) of 1-azabicyclo [2.2.2] octane-3-amine (3-aminoquinuclidine) was added. The mixture was stirred overnight at room temperature and evaporated to dryness. The residue was partitioned between ether and dilute hydrochloric acid. The aqueous phase was basified with potassium carbonate and extracted with ethyl acetate. Dry (Na ₂ S
O ₄ ) the evaporated ethyl acetate phase was evaporated and the residue (1.64 g) was
Changed to 1: 1 oxalate, 1/4 hydrate. 208-209 ° C
(Disassembly).

Example 2 N-[[[[1-azabicyclo [2.2.2] octane-3-
Yl] amino] carbonyl] -3,5-dichlorobenzamide 1.26 g of 3-aminoquinuclidine (10
Mmol) and 3,5-dichlorobenzoyl urea 2.2 g
(9.44 mmol) was stirred and refluxed under nitrogen overnight, filtered hot and cooled to room temperature. The precipitated solid was collected, washed with ethyl acetate, and dried to give 0.93 g of the title compound, which was converted into its hydrochloride and monohydrate. 253-254 ° C.

Example 3 (endo) -N- (3.5-dichlorobenzoyl) -O-
(8-Methyl-8-azabicyclo [3.2.1] oct-3
-Yl) carbamate 1 g (7.09 mmol) of tropine is dissolved in 10 ml of dichloromethane and then treated with 1.6 g (7.34 mmol) of 3,5-dichlorobenzoyl isocyanate in 8 ml of dichloromethane to give a clear solution which is obtained under nitrogen. Left overnight.
Methanol was added, the solution was evaporated and the residue was triturated with ether to give 1.62 g of product. This is triturated in 40 ml of refluxing acetonitrile for about 30 minutes, collected, dried and the compound containing 1/6 mole of acetonitrile
0.32 g was obtained. Mp 175-177 ° C.

Example 4 N- (3,5-dichlorophenyl) -N '-(1,2-diethylpyrazolidin-4-yl) urea 1.26 g of 4-amino-1,2-diethylpyrazolidine in 5 ml of aqueous toluene (8.8 mmol) in dry toluene
1.71 g of 3,5-dichlorophenyl isocyanate in 20 ml
(9.1 mmol) and the mixture was stirred overnight. The precipitated solid was collected, washed with toluene and dried to give 1.94g of the title compound. This was changed to 1: 1 maleate. Mp 165-167 ° C.

Example 5 N-[[[[1-azabicyclo [2.2.2] octane-3-
Yl] amino] carbonyl] -2-methoxybenzamide (a) 2-methoxybenzoyl isocyanate 2.27 g (15.04 mmol) of 2-methoxybenzamide and 2.4 g (18.9 mmol) of oxalyl chloride in 40 ml of 1,2-dichloroethane at reflux temperature And heated together for 16 hours. The resulting solution is concentrated under reduced pressure and the residue is re-evaporated with toluene to give an oily crude acyl isocyanate.
2.94 g were obtained.

(B) N-[[[1-Azabicyclo [2.2.2] octan-3-yl] amino] carbonyl] -2-methoxybenzamide This compound is obtained by adding 0.63 g (5 mmol) of 3-aminoquinuclidine and Methoxybenzoyl isocyanate
Prepared according to the procedure of Example 1 using 1.0 g (5 mmol) to obtain 1.6 g of the crude title product, which is purified as the 1: 1 fumarate salt. 187-188 ° C (0.79 g).

Example 6 N- (Azabicyclo [2.2.2] octan-3-yl)-
N ′-(3,5-dichlorophenyl) thiourea 1.0 ml (1.51 g, 13.13 mmol) of thiophosgene in 10 m of water
and stirred vigorously while adding 1.62 g (10 mmol) of 3.5-dichloroaniline in 8 ml of chloroform over 1 minute. 1.4 g (13.86 mmol) of triethylamine were added and stirring was continued for 30 minutes.

 The aqueous phase was discarded, leaving the chloroform phase.

1.99 g (10 mmol) of 3-aminoquinuclidine dihydrochloride were dissolved in 2 ml of water and treated with sodium hydroxide pellets until the pH was 9. This solution was then added to the chloroform solution and the two were stirred together overnight.

The aqueous phase was extracted three times with chloroform. The combined organic phases were washed once with water. An insoluble oil separated. The chloroform solution was dried (Na ₂ SO ₄ ), evaporated and the residue was combined with an insoluble oil. This material was triturated with dichloromethane for 3 hours and the title compound 2.0 as the hydrochloride salt with 0.5 mole of dichloromethane which could not be removed by drying.
9 g were obtained. 137-140 ° C.

Example 7 Endo-N- (3,5-dichlorophenyl) -N '-(8
-Methyl-8-azabicyclo [3.2.1] octane-3-
Il) Urea 0.94 g (5 mmol) of 3,5-dichlorophenylisocyanate and (endo) -8 according to the procedure of Example 1.
-Methyl-8-azabicyclo [3.2.1] octane-3-
The compound was prepared from 0.70 g (5 mmol) of the amine (3-aminotropane). The product was isolated as a 1: 1 maleate salt (0.58 g). 208-210 ° C.

Example 8 N- (1-azabicyclo [2.2.2] octan-3-yl) -N '-(3-trifluoromethylphenyl) urea Following the procedure of Example 1, 3-aminoquinuclidine 0.63
The compound was prepared from g (5 mmol) and 0.94 g (5 mmol) of 3-trifluoromethylphenyl isocyanate. The product was isolated as the hydrochloride salt (1.02g). 245-247 ° C.

Example 9 N- (1-Azabicyclo [2.2.2] octan-3-yl) -N '-(4-chlorophenyl) urea According to the procedure of Example 1, 3-aminoquinuclidine was used.
The compound was prepared from 63 g (5 mmol) and 0.768 g (5 mmol) of 4-chlorophenylisocyanate. The product was purified as 1.23 g of 1: 1 maleate. 182-183 ° C (decomposition).

Example 10 N- (1-Azabicyclo [2.2.2] octan-3-yl) -N '-(1-methyl-1H-indol-3-yl) urea According to the procedure of Example 1, 3-aminoquinucuria was used. Gin 0.96
g (7.62 mmol) and 1-methyl-3-isocyanatoindole (1.5 g of 1-methylindole-3-carbonylazide prepared by reaction of 1-methylindole-3-carboxylic acid with diphenylphosphoryl azide (7.
5 mmol)). The product was isolated as 0.32 g of 1: 1 oxalate, 1/3 2-propanol. Melting point (double) 120-124 ℃, 13
0-132 ° C.

Example 11 N- (1-Azabicyclo [2.2.2] octan-3-yl) -N '-(2-benzothienyl) urea Following the procedure of Example 1, 3-aminoquinuclidine 0.53
The compound was prepared from g (4.21 mmol) and 0.73 g (4.17 mmol) of 2-isocyanatobenzothiophene. The product was isolated as 0.18 g of 1: 1 oxalate, 1/4 hydrate. 204-206 ° C.

Example 12 (S)-(-)-N- (1-Azabicyclo [2.2.2] octan-3-yl) -N '-(3,5-dichlorophenyl) urea (a) (3S) -3- [ (S) -α-methylbenzylamino] quinuclidine 3-quinuclidinone hydrochloride 80.5 g (0.5 mol), (S)
A mixture of 180 g (1.49 mol) of α-methylbenzylamine, 31 g (0.5 mol) of sodium borohydride, 75 g of 3 molecular sieve, 750 ml of methanol and a sufficient amount of hydrogen chloride gas to bring the pH to about 6; 6 in water, adding hydrogen chloride if necessary to maintain pH 6.
Stirred for hours then at room temperature overnight. Filter the mixture,
The filtrate was evaporated. The residue was dissolved in water, basified with potassium hydroxide and extracted with ethyl acetate. The ethyl acetate extracts were dried (Na ₂ SO _4), evaporated and distilled. Boiling point 138
The product fraction at 142142 ° C. (2 mbar) was fractionally crystallized as its hydrochloride, 29.22 g of the title compound
I got 238-242 ° C (phase change 193-200 ° C).

(B) (S)-(-)-3-Aminoquinuclidine 24.38 g (91.5 mmol) of (3S) -3-[(S) -α-methylbenzylamino] quinuclidine hydrochloride in 80 ml of water
And glacial acetic acid at 130C and 40p on 1.2g of 10% Pd / C.
The hydrogen was added to si (about 2.7 × 10 ⁵ Pa). Filter the mixture,
The filtrate was treated with 10 ml of concentrated hydrochloric acid and evaporated. The residue is tolturated with isopropanol, dihydrochloride of the title compound 1
6.6 g were obtained. From the isopropanol mother liquor, a second yield of 0.5 g of dihydrobromide, mp 273-280, was obtained by treating with excess hydrogen bromide and concentrating to low volume until crystals precipitated.
° C (phase change> 240 ° C), [α] ²⁵ _D = -16 ° (c = 1, H ₂
O) was obtained.

(C) (S)-(-)-N- (1-azabicyclo [2.2.
2) Octan-3-yl) -N '-(3,5-dichlorophenyl) urea According to the procedure of Example 1, 1.98 g (15.71 mmol) of (S) -3-aminoquinuclidine and 3,5-dichlorophenylisocyanate The compound was prepared from 2.96 g (15.74 mmol) to give 0.95 g of the title compound. Melting point 200-201
° C, [α] ²⁵ _D = -21 ° (c = 1, CHCl ₃ ).

Example 13 (R)-(+)-N- (1-Azabicyclo [2.2.2] octan-3-yl) -N '-(3,5-dichlorophenyl) urea (a) (3R) -3- [ (S) -α-methylbenzylamino] quinuclidine (3S) -3- of the preparation obtained in Example 12a
From the mother liquor of [(S) -α-methylbenzylamino] quinuclidine hydrochloride, the product was obtained by fractional crystallization as 44.8 g of 1: 1 di-p-toluoyl-L-tartrate.
172-174 ° C.

(B) (R)-(+)-3-Aminoquinuclidine (3R) -3-[(S) -α-methylbenzylamino]
Quinuclidine di-p-toluoyl-L-tartrate 39.7
g (62.6 mmol) was partitioned between 200 ml of ether and 50 ml of 5M aqueous potassium hydroxide solution. The aqueous phase was extracted again with ether and the combined ether phases were dried (Na ₂ SO ₄ ) and evaporated. The residue was purified on 10 g of 10% Pd / C in 130 ml of glacial acetic acid at 50 ° C., 4
Hydrogenation was performed at ⁵ psi (about 3.1 × 10 ⁵ Pa). The mixture was worked up as in Example 12b to give 10.1 g of the dihydrochloride of the title compound, and for 0.5 g of the second yield of dihydrobromide, [α] ²⁵ _D =
+16.5 ゜ (c = 1, H ₂ O), melting point 284-285 ° C. (phase change> 2
30 ° C).

(C) (R)-(+)-N- (1-azabicyclo [2.2.
2] Octan-3-yl) -N '-(3,5-dichlorophenyl) urea According to the procedure of Example 1, 1.26 g (10 mmol) of (R) -3-aminoquinuclidine and 3,5- The above compound was prepared from 1.88 g (10 mmol) of dichlorophenyl isocyanate, and 1.35 g of a 1/4 hydrate of the title compound, melting point 190-194.
° C (forms rubber at 180-183 ° C), [α] ²³ _D
= + 23 ° (c = 1, CHCl ₃ ).

Example 14 N-[[[1-Azabicyclo [2.2.2] octane-3-
[Ill] amino] carbonyl-3-trifluoromethylbenzamide (a) N-trifluoromethylbenzoylurea A mixture of 10 g (52.6 mmol) of 3-trifluoromethylbenzoic acid and 15 ml of thionyl chloride was heated under reflux for 0.75 hours. The excess thionyl chloride is evaporated and 10 g of urea (1
67 mmol) was added to the residue and the mixture was treated at 100-110 ° C. with 1.
Heated for 5 hours. The solid was extracted under reflux with 20 ml of water, cooled, basified with sodium bicarbonate, and the solid was collected and recrystallized from aqueous acetic acid to give 8 g of product. Melting point 19
1-193 ° C.

(B) N-[[[1-Azabicyclo [2.2.2] octan-3-yl] amino] carbonyl-3-trifluoromethylbenzamide 3-aminoquinuclidine dihydrochloride in 20 ml of pyridine 1.
0 g (5 mmol), 3-trifluoromethylbenzoyl urea 1.16 g (5 mmol) and diisopropylamine
The compound was prepared from 1.29 g (10 mmol) by refluxing under nitrogen overnight. The solvent was evaporated and the residue was worked up as in Example 1. 1.18 g of product was converted to oxalate. 197-200 ° C.

Example 15 N-[[[1-Azabicyclo [2.2.2] octane-3-
Yl] amino] carbonyl] -4-methoxybenzamide 1.0 g (5 mmol) of 3-aminoquinuclidine dihydrochloride, 0.97 g (5 mmol) of 4-methoxybenzoylurea and diisopropyl in 20 ml of pyridine according to the procedure of Example 14b. The compound was prepared from 1.29 g (10 mmol) of ethylamine. 1.12 g of the product is 1: 1 maleic acid, 1 /
Changed to dihydrate. Melting point 166-168 [deg.] C.

Example 16 N-[[[1-Azabicyclo [2.2.2] octane-3-
Yl] amino] carbonyl] naphthalene-2-carboxamide (a) 2-naphthoylurea According to the procedure of Example 14a, the above compound was prepared from 8.2 g (47.7 mmol) of naphthoic acid, 40 ml of thionyl chloride and 10 g (167 mmol) of urea. Prepared 7.1 g of the title compound. 207-208 ° C.

(B) N-[[[1-Azabicyclo [2.2.2] octan-3-yl] amino] carbonyl] naphthalene-2-carboxamide According to the procedure of Example 14b, 3-aminoquinuclidine dihydrochloride in 20 ml of pyridine. The compound was prepared from 1.0 g (5 mmol) of the salt, 1.07 g (5 mmol) of 2-naphthoylurea and 1.29 g (5 mmol) of diisopropylethylamine. The title compound was isolated as the hydrochloride salt, hemihydrate 1.39 g. 271-273 ° C (decomposition).

Example 17 N-[[[1-Azabicyclo [2.2.2] octane-3-
Yl] amino] carbonyl] -2-furancarboxamide Following the procedure of Example 14b, 1.0 g (5 mmol) of 3-aminoquinuclidine dihydrochloride, 0.77 g (5 mmol) of 2-furoylurea and diisopropyl in 20 ml of pyridine. The compound was prepared from 1.3 g (10 mmol) of ethylamine. 0.58 g of product was converted to 1: 1 succinate. Melting point 15
6-159 ° C.

Example 18 N-[[[[1-azabicyclo [2.2.2] octane-3-
Yl] amino] carbonyl] -2,6-dimethylbenzamide (a) 2,6-dimethylbenzoylurea 10 g of 2,6-dimethylbenzoic acid according to the procedure of Example 14a.
(66.7 mmol), 15 ml of thionyl chloride and 10 g of urea (1
68 mmol) to produce the title compound.
9 g were obtained. 210-213 ° C.

(B) N-[[[1-Azabicyclo [2.2.2] octan-3-yl] amino] carbonyl] -2,6-dimethylbenzamide According to the procedure of Example 14b, 3-aminoquinuclidinediamine in 20 ml of pyridine. The compound was prepared from 1.0 g (5 mmol) of the hydrochloride, 0.96 g (5 mmol) of 2,6-dimethylbenzoylurea and 1.3 g (10 mmol) of diisopropylethylamine by refluxing for 4 days. The product was recrystallized from acetonitrile to give 0.54 g of a 1/4 hydrate of the title compound. 230-231 ° C.

Example 19 N-[[[1-Azabicyclo [2.2.2] octane-3-
Yl] amino] carbonyl] -2-thiophenecarboxamide Following the procedure of Example 14b, 1.0 g (5 mmol) of 3-aminoquinuclidine dihydrochloride, 0.85 g (5 mmol) of 2-thienoylurea and diisopropyl in 20 ml of pyridine. The compound was prepared from 1.3 g (10 mmol) of ethylamine. The product, 0.79 g, was converted to the hydrochloride, hemihydrate. 232-233 ° C.

Example 20 N-[[[1-Azabicyclo [2.2.2] octane-3-
Yl] amino] carbonyl] -2-fluorobenzamide (a) 2-fluorobenzoyl isocyanate According to the procedure of Example 5a, 1,2-dichloroethane 20 ml
Medium, 2-fluorobenzamide 0.97 g (6.98 mmol)
The compound was prepared from 1.08 g (8.36 mmol) of oxalyl chloride and 1.3 g of crude product.

(B) N-[[[1-Azabicyclo [2.2.2] octan-3-yl] amino] carbonyl] -2-fluorobenzamide According to the procedure of Example 1, 3-aminoquinuclidine 0.63
The compound was prepared from g (5 mmol) and 1.3 g (about 7 mmol) of crude 2-fluorobenzoyl isocyanate. 1.35 g of product was converted to 1: 1 succinate. 187-188 ° C.

Example 21 N-[[[1-Azabicyclo [2.2.2] octane-3-
Yl] amino] carbonyl] -2-ethoxybenzamide (a) 2-ethoxybenzoyl isocyanate According to the procedure of Example 5a, 1,2-dichloroethane 20 ml
Medium, 2-ethoxybenzamide 1.15 g (6.97 mmol)
The above compound was prepared from 1.08 g (8.36 mmol) of oxalyl chloride, and 1.59 g of a crude product was obtained.

(B) N-[[[1-Azabicyclo [2.2.2] octan-3-yl] amino] carbonyl] -2-ethoxybenzamide According to the procedure of Example 1, 3-aminoquinuclidine 0.63
The compound was prepared from g (5 mmol) and 1.59 g (about 7 mmol) of crude 2-ethoxybenzoyl isocyanate. 1.77 g of product was converted to 1: 1 fumarate. Melting point 198-199 [deg.] C.

Example 22 N-[[[[1-Azabicyclo [2.2.2] octane-3-
Yl] amino] carbonyl] -2-isopropoxybenzamide (a) 2-isopropoxybenzoyl isocyanate 10 ml of 1,2-dichloroethane according to the procedure of Example 5a.
The above compound was prepared from 0.44 g (2.46 mmol) of 2-isopropoxybenzamide and 0.38 g (2.97 mmol) of oxalyl chloride, to obtain 0.58 g of a crude product.

(B) N-[[[1-Azabicyclo [2.2.2] octan-3-yl] amino] carbonyl] -2-isopropoxybenzamide According to the procedure of Example 1, 3-aminoquinuclidine 0.31
The compound was prepared from g (2.46 mmol) and 0.58 g (about 2.5 mmol) of crude 2-isopropoxybenzoyl isocyanate. 0.51 g of product was converted to 1: 1 fumarate. Mp 171-175 ° C.

Example 23 2-allyloxy-N-[[[1-azabicyclo [2.2.
2] octan-3-yl] amino] carbonyl] benzamide (a) 2-allyloxybenzoyl isocyanate 10 ml of 1,2-dichloroethane according to the procedure of Example 5a.
The above compound was prepared from 0.39 g (2.2 mmol) of 2-allyloxybenzamide and 0.35 g (2.74 mmol) of oxalyl chloride, to obtain 0.35 g of a crude product.

(B) 2-allyloxy-N-[[[1-azabicyclo [2.2.2] octan-3-yl] amino] carbonyl]
Benzamide According to the procedure of Example 1, 3-aminoquinuclidine 0.28
The compound was prepared from g (2.2 mmol) and 0.53 g (about 2.2 mmol) of 2-allyloxybenzoyl isocyanate. 0.61 g of product was converted to 1: 1 fumarate.

Example 24 N-[[[1-Azabicyclo [2.2.2] octane-3-
[Ill] amino] carbonyl] -2-pyridinecarboxamide (a) A mixture of 0.23 g (10 mmol) of sodium 2-pyridoylurea, 0.8 g (13.3 mmol) of urea and 40 ml of liquid ammonia was stirred until the blue color disappeared. 2.85 g (18.8 mmol) of ethyl 2-pyridinecarboxylate were all added immediately. 1
After time, the ammonia was evaporated and the residue was triturated with water to give the compound. 183-185 ° C.

(B) N-[[[1-Azabicyclo [2.2.2] octan-3-yl] amino] carbonyl] -2-pyridinecarboxamide According to the procedure of Example 14b, 3-aminoquinuclidine dihydrochloride in 20 ml of pyridine. The compound was prepared from 1.0 g (5 mmol) of the salt, 0.82 g (5 mmol) of 2-pyridoylurea and 1.3 g (10 mmol) of diisopropylethylamine by refluxing for 4 days. The pyridine was evaporated and the residue was partitioned between ether and 10% aqueous w / v citric acid. The mixture was filtered, the aqueous phase was washed with ether, then basified with potassium carbonate, causing 0.60 g of the title compound to precipitate, which was converted to the fumarate.

Example 25 Endo-N-[[[8-methyl-8-azabicyclo [3.
2.1] Octane-3-yl] amino] carbonyl] -2
-Methoxybenzamide Endo-3-aminotropane according to the procedure of Example 1.
The compound was prepared from 0.70 g (5 mmol) and 1.0 g (5 mmol) of 2-methoxybenzoyl isocyanate. The product 2.1 g (crude) was changed to the hydrochloride salt 0.65 g.

Example 26 N-[[[1-Azabicyclo [2.2.2] octane-3-
Yl] amino] carbonyl] -2-methylbenzamide (a) 2-methylbenzoyl isocyanate According to the procedure of Example 5a, 1,2-dichloroethane 20 ml
The above compound was prepared from 0.95 g (7 mmol) of 2-methylbenzamide and 1.08 g (8.36 mmol) of 2-methylbenzamide in the above to give 1.35 g of a crude product.

(B) N-[[[1-Azabicyclo [2.2.2] octan-3-yl] amino] carbonyl] -2-methylbenzamide According to the procedure of Example 1, 3-aminoquinuclidine 0.63
The compound was prepared from g (5 mmol) and 1.35 g (about 7 mmol) of crude 2-methylbenzoyl isocyanate. 1.23 g of product was converted to 1: 1 fumarate.
216-217 ° C.

Example 27 N-[[[1-Azabicyclo [2.2.2] octane-3-
Yl] amino] carbonyl] -2-((cyclopropyl) methoxy) benzamide (a) 2-((cyclopropyl) methoxy) benzamide 5.17 in 2-ethanol ethanol 5.17
g (37.74 mmol) and sodium hydroxide 1.5 g (37.5
Mmol) was refluxed for 1 hour to give a clear solution. 5.09 g (37.7 mmol) of (bromomethyl) cyclopropane were added and the mixture was refluxed for 36 hours. The solvent was evaporated and the residue was triturated well with ether and water to give 4.37 g of the compound.

(B) 2-((cyclopropyl) methoxy) benzoyl isocyanate According to the procedure of Example 5a, 1,2-dichloroethane 20 ml
Medium, 2-((cyclopropyl) methoxy) benzamide
0.95 g (5 mmol) and 0.79 g oxalyl chloride (6.2
Mmol) to give 1.4 g of crude product
I got

(C) N-[[[1-Azabicyclo [2.2.2] octan-3-yl] amino] carbonyl] -2-((cyclopropyl) methoxy) benzamide According to the procedure of Example 1, 3-aminoquinuclidine 0.63
g (5 mmol) and crude 2-((cyclopropyl)
The compound was prepared from 1.4 g (about 5 mmol) of methoxy) benzamide. The product was changed to 1: 1 oxalate, hemihydrate. 128-131 ° C.

Example 28 (S) -N-[[[1-Azabicyclo [2.2.2] octan-3-yl] amino] carbonyl] -2-methoxybenzamide According to the procedure of Example 1, (S) -3-aminoquinone The compound was prepared from 0.63 g (5 mmol) of pyridine and 1.26 g (7 mmol) of 2-methoxybenzoyl isocyanate. 1.44 g of the product was converted to 1: 1 fumarate. 158-159 ° C (decomposition).

Example 29 (R) -N-[[[1-Azabicyclo [2.2.2] octan-3-yl] amino] carbonyl] -2-methoxybenzamide According to the procedure of Example 1, (R) -3-aminoquinone The compound was prepared from 0.63 g (5 mmol) of pyridine and 1.33 g (7.5 mmol) of 2-methoxybenzoyl isocyanate. 1.49 g of product was converted to 1: 1 fumarate. 158-159 ° C (decomposition).

Example 30 (endo) -O- [8-methyl-8-azabicyclo [3.
2.1] Octan-3-yl] -N- (3,5-dichlorophenyl) carbamate 1.0 g (7.04 mmol) of tropine was added at room temperature under nitrogen at room temperature to 1.32 g (7.02 mmol) of 3,5-dichlorophenylisocyanate in 20 ml of dichloromethane. ). The reaction mixture was stirred for 20 hours and the solid was collected and partitioned between ether and dilute hydrochloric acid. The insoluble solid was collected, washed with dilute hydrochloric acid and then with ether, and 0.73 g of the compound as its hydrochloride.
I got 288-294 ° C (decomposition).

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication // A61K 31/415 AEN A61K 31/415 AEN 31/435 AAE 31/435 AAE AAH AAAH AAN AAN 31 / 44 ACJ 31/44 ACJ 31/46 ACP 31/46 ACP

Claims (3)

(57) [Claims] (1) Formula: AX-NHCW-YB (I) wherein A is a formula: [The free valence is bonded to a condensed ring of either formula (a) or (b).] Wherein R ¹ is hydrogen or lower alkyl, lower alkoxy [the lower alkoxy is lower alkyloxy, cycloalkyl (Lower) alkyloxy, cyclo (lower) alkyl-lower alkyloxy, (lower) alkenyl (lower) alkyloxy and halo (lower) alkyloxy], hydroxy, halogen, halo (lower) alkyl, amino, A nitro, carboxamido, phenyl group optionally substituted with one or more lower alkyl, lower alkyloxy or halogen substituents, phenyl (lower) alkyloxy, (lower) alkylamino, di (lower) alkyl One or more identical or different substituents selected from amino or acylamino, Z ^1-
Z ² is ^{_{CH 2 -CH, NR 2 -CH,}} O-CH, S-CH, CH 2 -N, O
-N, SN, NR ² -N, CH-NR ² or N-NR ² , R ² is hydrogen, (lower) alkyl or phenyl group optionally having one or more lower alkyl, lower alkyloxy or Phenyl or phenyl (lower) alkyl optionally substituted by a halogen substituent, Z ³ -Z ⁴ is CH = CH,
O-CH ₂ or N = CH, Z ⁵ is N or CH and Z ⁶ is O,
Wherein X is a direct bond or CO, W is oxygen or sulfur, Y is NH or O, and B is a compound of formula (II): Wherein n is 2, 3 or 4 and R ³ is hydrogen or (lower) alkyl, formula (III): Or its N-oxide, formula (IV): (Wherein m is 1, 2 or 3 and R ³ is the same as above),
Formula (V): (Wherein p represents 0, 1 or 2), or formula (VI): Wherein R ⁴ and R ⁵ each represent hydrogen or lower alkyl, wherein X is a direct bond, and A is a compound of formula (c) or (d) And W is oxygen, ring (c) or (d) is -X-NH
Having no substituent at the ortho-position to the CW-YB side chain] or a pharmaceutically acceptable acid addition salt thereof. (2) N- (1-azabicyclo [2.2.2] octan-3-yl) -N '-(3,5-dichlorophenyl) urea or a pharmaceutically acceptable salt thereof. The compound of the item 1). 3. The method according to claim 1, wherein the compound is N-[[[1-azabicyclo [2.2.2] octan-3-yl) amino] carbonyl] -2-methoxybenzamide or a pharmaceutically acceptable salt thereof. )).